Blood Test Identifies Individuals at Risk of Developing Parkinson’s Disease Before Symptoms Occur

A significant challenge in conducting clinical trials for disease modification is identifying individuals in the earliest stages of disease development and excluding those with similar symptomatology but different conditions. Parkinson's disease begins more than a decade before symptoms become clinically evident, which can be attributed to brain cells' inability to process a small protein known as alpha-synuclein. This dysfunction leads to the formation of abnormal alpha-synuclein clusters that harm susceptible nerve cells, resulting in the well-known movement disorder and frequently dementia. By the time of diagnosis, most of these sensitive nerve cells have perished, and alpha-synuclein aggregates are present in numerous brain regions. A predictive method for identifying impairments in alpha-synuclein pathways before Parkinson’s symptoms occur would be invaluable, aiding clinicians in identifying individuals who might benefit most from upcoming disease-modifying treatments.

At the University of Oxford (Oxford, UK), researchers have developed a novel blood test capable of detecting Parkinson’s disease pathology before the onset of its primary symptoms. This advancement paves the way for early identification of individuals at heightened risk of developing the disease, thereby facilitating the prompt application of precision therapies currently under clinical investigation. The study highlights the potential of measuring a specific subtype of extracellular vesicles to identify changes in alpha-synuclein in individuals predisposed to Parkinson's disease. Extracellular vesicles, nanoparticles released by all cell types and present in various biofluids including blood, transport molecular signals between cells. Employing a refined antibody-based assay created by the research team, the test isolates nerve cell-derived extracellular vesicles from blood samples, measuring their alpha-synuclein content.

In this pioneering study, the research team examined 365 at-risk individuals from four clinical cohorts, 282 healthy controls, and 71 individuals with either genetic or sporadic Parkinson's disease. The study revealed that those with the highest Parkinson’s risk (over 80% probability based on research criteria) exhibited a twofold increase in alpha-synuclein within neuronal extracellular vesicles. The test successfully differentiated these individuals from low-risk and healthy controls. It could distinguish a high-risk individual from a healthy control with 90% probability. This suggests that the blood test, combined with limited clinical assessment, could effectively screen and identify high-risk individuals. The test could also identify individuals who had evidence of neurodegeneration detected by imaging, or pathology detected by a spinal fluid assay, but were yet to develop a movement disorder or dementia

In a smaller subgroup of 40 people who eventually developed Parkinson’s and related dementia, the blood test was positive in over 80% of cases up to seven years prior to diagnosis. This group showed a correlation between higher blood alpha-synuclein levels in neuronal extracellular vesicles, lower spinal fluid alpha-synuclein levels, and a longer duration before the emergence of main Parkinson's symptoms. This implies that nerve cells might protect themselves by packaging excess alpha-synuclein in extracellular vesicles, subsequently released into the blood. Building on prior research by the same team, the current study confirms that this biomarker is elevated in Parkinson’s patients but not in other conditions with Parkinson's-like symptoms. The researchers had earlier outlined the pathway targeting alpha-synuclein for degradation within nerve cells. This pathway might also channel alpha-synuclein outside cells in extracellular vesicles, particularly when intracellular protein turnover is compromised in conditions like aging and Parkinson’s disease.

“Collectively our studies demonstrate how fundamental investigations in alpha-synuclein biology can be translated into a biomarker for clinical application, in this case for the identification and stratification of Parkinson’s risk,” said Professor George Tofaris. “A screening test that could be implemented at scale to identify the disease process early is imperative for the eventual instigation of targeted therapies as is currently done with screening programs for common types of cancer.”

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